Mutations in p53 are thought to occur in more than 50% of human cancers and are most frequently observed in the DNA binding and transactivation domains, underscoring the importance of its transcriptional activity in suppressing tumor development. In sporadic breast cancers, unlike most cancer types, p53 mutations are only observed in approximately 20% of cases. However, that breast cancer is frequently observed in individuals with germline mutations of p53 (i.e., Li-Fraumeni syndrome) suggests a particularly important role for p53 inactivation in breast carcinogenesis, and perhaps a similarly important role for other factors capable of compromising p53 function.
For example, the reduced transcriptional activation of p53 following hypermethylation and subsequent inhibition of the HOXA5 transcription factor has recently been implicated as a possible epigenetic mechanism in reducing p53 expression in breast cancers. In both breast tumors and other cancer types, amplification and overexpression of the MDM2 gene, whose product promotes p53 degradation, has been implicated in oncogenesis. Moreover, both deletion and epigenetic silencing of the p14ARF gene, a negative regulator of MDM2, has been observed in various cancer types. Thus, p53 deficiency in breast carcinogenesis can potentially arise from a number of mechanisms other than p53 gene mutation.
There is evidence that the p53 status has prognostic significance in a number of cancer types and in particular breast cancer. In breast cancer, p53 mutations confer worse overall and disease-free survival, and a higher incidence of tumor recurrence, independent of other risk factors. Recent evidence suggests that p53 inactivation renders breast tumors resistant to certain DNA-damaging chemotherapies and endocrine therapies presumably through loss of p53-dependent apoptosis.
However, in all of these studies, the prognostic capability and degree of therapeutic resistance of the p53 mutants was found to depend largely on mutant-specific attributes, such as the type of mutations or the precise domain in which the mutation occurs. Importantly, this latter observation is consistent with findings from previous studies showing that not all p53 mutations have equal effects: some simply confer loss of function, while others have a dominant negative effect (such as trans-dominant suppression of wildtype p53 or oncogenic gain of function), while still others show only a partial loss of function where, for example, only a small subset of p53 downstream transcriptional target genes are dysregulated. For these reasons, no single molecular assessment of p53 status appears to provide an absolute indication of the complete p53 function.
There is a need for methods that better assess the effects of different p53 mutations on cell function in general and gene expression in particular, in an effort to enable better cancer prognosis and diagnosis.